PROJECT SUMMARY/ABSTRACT Neurofibromatosis type 1 (NF1) is a common inherited genetic disorder with a variety of symptoms, most commonly as neurocutaneous lesions and developmental disorders, and less commonly with tumors. Cognitive symptoms such as attentional deficits affect up to 80% of patients, with diagnosis of attention deficit hyperactivity disorder (ADHD) estimated at 50% in NF1 patients. Unlike the general population, attention deficits affect boys and girls equally in NF1. Few studies have investigated the underlying mechanisms contributing to high incidence of ADHD diagnosis in NF1. Using a murine experimental model system of NF1, mice haploinsufficient for the NF1 gene (Nf1+/-), our preliminary data in male mice show deficits in behavioral inhibition, a key component of ADHD, as exhibited by hyperactivity in open field, increased fall frequency in cliff avoidance reaction task, and increased frequency of small reward choice in delay discounting task, rescuable by ADHD medication (guanfacine 0.3 mg/kg, i.p.) administration. The first aim of this proposed study will elucidate the brain mechanisms underlying deficits in behavioral inhibition, and will be powered to detect male and female differences in behavior and corresponding measures of circuitry activity including in vivo recordings in the prefrontal cortex. In the second aim, we propose a genetic rescue for these observed behavioral inhibition deficits. NF1 is caused by reduced levels of neurofibromin, a RAS GTPase-activating protein, resulting in RAS-MAPK-ERK hyperactivation. Currently, there are no available treatments for cognitive deficits in NF1 that target RAS-MAPK-ERK hyperactivation. This project, proposes a novel mechanism for treatment of cognitive deficits in NF1 by restoring neurofibromin levels through modulation of the ubiquitin-proteasome pathway. Overall, this project will characterize clinically relevant circuits underlying behavioral inhibition deficits, a key feature of ADHD, in males and females. Additionally, this proposal will address the need for a treatment target in NF1 that has the potential to address the many symptoms patients may experience including cognitive deficits, tumors, and neurocutaneous symptoms. Modulation of the neurofibromin ubiquitin- proteasome pathway may provide a novel and safer pharmacologic target for treating NF1.